Although our understanding of the structure and function of the nervous system has greatly advanced in recent years, a need still exists for efficacious treatments of many neurological disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, schizophrenia, severe pain, multiple sclerosis, bipolar disease, and diseases of the nervous system caused by infection by viruses and other microorganisms (herpes simplex, HIV, cytomegalovirus, parasites, fungi, prions, etc.).
Many neuropharmaceutical agents have been developed to treat diseases of the nervous system, but their usefulness has been hampered by severe side effects partially due to nonspecific interactions between these agents and cells or tissues other than the targeted cells. For example, the corticosteroid hormone cortisone (4-pregnen-17α, 21-diol-3,11,20-trione) and its derivatives are widely used to treat inflammation in the body including the nervous system to reduce symptoms such as swelling, tenderness and pain. However, the steroid dosage has to be kept at the lowest effective level because of its severe side effects. Steroid hormones like cortisone bind to their cognate nuclear hormone receptors and induce a cascade of cellular effects, including programmed cell death of the neurons in the brain (Kawata et al., J. Steroid Biochem. Mol. Biol. 65: 273-280 (1998)). Since steroid hormone receptors, such as the glucocorticoid receptor for cortisone, are distributed in a wide variety of tissues and cells, nonspecific interactions of the hormone with its cognate receptor in different sites is unavoidable if the drug is circulated systemically.
A need thus continues to exist for an effective system for delivering therapeutic agents selectively to nerve cells and nerve tissues. Various techniques have been developed to deliver drugs selectively, but with only limited success.
For example, liposomes have been used as carrier molecules to deliver a broad spectrum of agents including small molecules, DNAs, RNAs, and proteins. Liposome mediated delivery of pharmaceutical agents has major drawbacks because of its lack of target specificity. Attempts have been made to overcome this problem by covalently attaching whole site-specific antibody or Fab fragments to liposomes containing a pharmaceutical agent (Martin et al., Biochem. 20, 4229-4238, (1981)). However, an intrinsic problem of particular importance in any liposome carrier system is that in most cases the targeted liposome does not selectively reach its target site in vivo. Whether or not liposomes are coated with antibody molecules, liposomes are readily phagocytosed by macrophages and removed from circulation before reaching their target sites.